Immune Thrombocytopenic Purpura

ITP, classically known as idiopathic thrombocytopenic purpura, is characterized by a low platelet count despite normal bone marrow and the absence of other causes of thrombocytopenia that could be responsible for the finding. Autoantibodies are responsible for the disordered platelet destruction mediated by the overactivated platelet phagocytosis within the reticuloendothelial system. Within the bone marrow, normal (or sometimes increased) amounts of megakaryocytes are present. There persists, however, a relative bone marrow failure in that production cannot match destruction to compensate sufficiently.

The typical presentation of ITP is characterized by purpura, epistaxis, and gingival bleeding. Less commonly, gastrointestinal bleeding and hematuria are noted. Intracerebral hemorrhage is a rare but sometimes fatal presentation. The diagnosis of ITP involves the exclusion of other relatively common causes of thrombocytopenia—pregnancy, drug-induced thrombocytopenia (e.g., heparin, quinidine, quinine, sulfonamides), viral infections, and hypersplenism (Box 57-2). Mild thrombocytopenia may be seen in approximately 6% to 8% of otherwise normal pregnancies and in up to 25% of women with preeclampsia. Drug-induced thrombocytopenia is thought to occur rarely, in approximately 20 to 40 cases/million users of common medications, such as trimethoprim-sulfonamide and quinine. Other medications, such as gold salts, have a higher incidence, almost 1% of users.⁷ Viral infection (e.g., hepatitis C virus [HCV], HIV, rarely, Epstein-Barr virus [EBV]) can be responsible for thrombocytopenia independent of splenic sequestration. Once again, other processes must be ruled out but health care providers can be confident of these causative factors if platelet counts improve with successful treatment of the responsible infection. Bacterial infection, specifically Helicobacter pylori, has also been linked to infection-related thrombocytopenia that improves with eradication. Other causes are listed in Box 57-2; spurious laboratory values caused by platelet clumping or the presence of giant platelets should not be ignored.

ITP is predominantly a disease of young women; 72% of patients older than 10 years of age are women and 70% of affected women are younger than 40 years. ITP manifests somewhat differently in children—both genders are affected equally, onset is sudden, thrombocytopenia is severe, and complete spontaneous remissions are seen in approximately 80% of affected children. Girls older than 10 years with more chronic purpura are those in whom the disease seems to persist.

Management of ITP depends primarily on the severity of the thrombocytopenia.⁸ Asymptomatic patients with platelet counts higher than 50,000/mm³ may be observed without further intervention. Platelet counts of 50,000/mm³ and higher are rarely associated with clinical sequelae, even with invasive procedures. Patients with slightly lower platelet counts, between 30,000 and 50,000/mm³, may always be observed but with more routine follow-up because they are at increased risk for progressing to severe thrombocytopenia. Initial medical treatment for patients with platelets counts less than 50,000/mm³ and symptoms such as mucous membrane bleeding, high-risk conditions (e.g., active lifestyle, hypertension, peptic ulcer disease), or platelet counts less than 20,000 to 30,000/mm³, even without symptoms, is glucocorticoid administration (typically, prednisone, 1 mg/kg body weight/day). Clinical response with increases in platelet levels to higher than 50,000/mm³ is seen in up to two thirds of patients within 1 to 3 weeks of initiating treatment. Of patients treated with steroids, 25% will experience a complete response. Patients with platelet counts higher than 20,000/mm³ who remain symptom-free, or who experience minor purpura as their only symptom, do not require hospitalization. Hospitalization may be required for patients whose platelets counts remain below 20,000/mm³ with significant mucous membrane bleeding and is required for those who have life-threatening hemorrhage. Platelet transfusion is indicated only for those who experience severe hemorrhage. IV immunoglobulin is important for the treatment of acute bleeding, in pregnancy, or for patients being prepared for operation, including splenectomy. The usual dose is 1 g/kg body weight/day for 2 days. This dose usually increases the platelet count within 3 days; it also increases the efficacy of platelet transfusions.

Prior to the establishment of glucocorticoids as treatment for ITP in 1950, splenectomy was the treatment of choice.⁸ For those two thirds of patients in whom glucocorticoids result in the normalization of platelet counts, no further treatment is necessary. For patients with severe thrombocytopenia, with counts less than 10,000/mm³ for 6 weeks or longer, those with thrombocytopenia refractory to glucocorticoid treatment, or those who require toxic doses of steroid to achieve remission, the treatment of choice is to proceed to splenectomy. Splenectomy is also the treatment of choice for patients with incomplete response to glucocorticoid treatment and for pregnant women in the second trimester of pregnancy who have also failed steroid treatment or IV Ig therapy with platelet counts less than 10,000/mm³ without symptoms or less than 30,000/mm³ with bleeding problems. It is not necessary to proceed to splenectomy for patients who have platelet counts higher than 50,000/mm³, have had ITP for longer than 6 months, are not experiencing bleeding symptoms, and who are not engaged in high-risk activities. A recent review of short-term and long-term failure of laparoscopic splenectomy has reported an overall approximate failure rate of 28% at 5 years after splenectomy.⁹

A systematic review of 436 published articles from 1966 to 2004 has reported that 72% of patients with ITP had a complete response to splenectomy. Relapse occurred in a median of 15% of patients (range, 1% to 51%), with a median follow-up of 33 months.¹⁰

In addition to relapse rates, predictors of successful splenectomy were examined. Of the variables in the multivariate model, age at the time of splenectomy was an independent variable that was most correlated with response.¹⁰ Younger patients had improved responses. Preoperative indium-111 (¹¹¹In)–labeled platelet scintigraphy with platelets sequestered predominantly within the spleen had a significantly higher response rate than those noted to have hepatic sequestration.¹¹

Most patients will exhibit improved platelet counts within 10 days postoperatively and durable platelet responses are associated with patients who have platelet counts of 150,000/mm³ by postoperative day 3 or more than 500,000/mm³ by the postoperative day 10. Even with splenectomy, however, some patients may relapse (~12%; range, 4% to 25%).¹² A recent review of 1223 ITP patients has estimated the long-term failure rate of laparoscopic splenectomy at approximately 8% and approximately 44/1000 patient-years of follow-up.⁹ Another study has estimated the complete response of ITP patients postsplenectomy to be 66%.¹⁰

Although a thorough search for accessory spleens is completed during the initial surgery, evaluation for a missed accessory spleen must be undertaken in patients who experience a relapse. In their evaluation of 394 patients treated with laparoscopic splenectomy, Katkhouda and colleagues¹² noted 15% of patients with accessory spleens. In those with accessory spleens, examination of a peripheral blood smear will lack the characteristic red cell morphology resulting from excision of the spleen. Radionuclide imaging may also be helpful in locating the presence and location of any accessory splenic tissue. Patients with chronic ITP in whom an accessory spleen is identified should have this removed, as long as the patient can withstand the surgical risk.

Other treatment options for these patients include observation of stable nonbleeding patients with platelet counts higher than 30,000/mm³, long-term glucocorticoid therapy, and treatment with azathioprine or cyclophosphamide. Recent evidence regarding thrombopoietin receptor agonists may offer a novel medical therapy for patients with no response to steroids, IV immunoglobulin therapy, or splenectomy.¹³

Other conditions linked to thrombocytopenia include thrombotic thrombocytopenic purpura, chronic disseminated intravascular coagulation, congenital thrombocytopenia, myelodysplasia, autoimmune disorders (e.g., systemic lupus erythematosus), and lymphoproliferative disorders (e.g., chronic lymphocytic leukemia, non-Hodgkin’s lymphoma).

Approximately 10% to 20% of otherwise asymptomatic patients with HIV will develop ITP. Splenectomy is a safe treatment option for this cohort of patients and may actually delay HIV disease progression.^14,15

Hereditary Spherocytosis

Hereditary spherocytosis is an autosomal dominant disease affecting the production of spectrin, a red blood cell cytoskeletal protein. Loss of this protein causes red blood cells to lack their characteristic biconcave shape. This affects the red blood cells’ deformability, because lack of this protein results in rigid erythrocytes that are small and sphere-shaped. Also, these cells have increased osmotic fragility and are more susceptible to trapping and destruction by the spleen. The resulting clinical features are anemia, occasionally with jaundice, and splenomegaly. Diagnosis is made by examination of a peripheral blood smear, increased reticulocyte count, increased osmotic fragility, and a negative Coombs’ test.

The resultant anemia can be successfully treated with splenectomy, but normalization of the erythrocyte morphology does not occur. Splenectomy should be delayed until the age of 5 years to preserve immunologic function of the spleen and reduce the risk of OPSI. Just as with other hemolytic anemias, the presence of pigmented gallstones is common. The preoperative workup should include ultrasound evaluation; if gallstones are present, cholecystectomy may be performed at the same time as splenectomy.

Hereditary elliptocytosis, hereditary pyropoikilocytosis, hereditary xerocytosis, and hereditary hydrocytosis also result in anemia secondary to red blood cell membrane abnormalities. Splenectomy is indicated in cases of severe anemia with these conditions, except hereditary xerocytosis, which results in only mild anemia of limited clinical significance.

Hemolytic Anemia Caused by Erythrocyte Enzyme Deficiency

Pyruvate kinase deficiency and glucose-6-phosphate dehydrogenase (G6PD) deficiency are the predominant hereditary conditions associated with hemolytic anemia. Pyruvate kinase deficiency is an autosomal recessive disease that results in decreased red blood cell deformability and the formation of echinocytes, a type of spiculated red blood cell. This morphologic variant increases the likelihood that the cell will be trapped and destroyed by the spleen, which results in splenomegaly, hemolytic anemia, and associated transfusion requirements, which can be mitigated with splenectomy. Again, for reasons discussed earlier, splenectomy is delayed until 5 years of age.

In G6PD deficiency, however, splenectomy is rarely indicated. This X-linked condition is typically seen in people of African, Middle Eastern, or Mediterranean ancestry. Hemolytic anemia in these patients most often occurs after infection or exposure to certain foods, medications, or chemicals. Primary treatment, therefore, is avoidance of exacerbation of the condition.

Hemoglobinopathies

In addition to defects of cellular membranes or enzymes, hereditary anemias may also result from defects in hemoglobin molecules. Sickle cell disease and thalassemia are two disorders in which the hemoglobin molecules exhibit qualitative or quantitative defects. These lead to abnormally shaped erythrocytes, which may lead to splenic sequestration and subsequent destruction.

Sickle cell anemia results from a single amino acid substitution (valine for glutamic acid) in the sixth position of the β chain of hemoglobin A, which causes those hemoglobin chains, under reduced oxygen conditions, to become rigid and unable to deform within the microvasculature. This rigidity causes the red cells to assume the elongated crescent or sickle shape. Sickle cell disease results from homozygous inheritance of the defective hemoglobin (hemoglobin S) although sickling can also be seen when hemoglobin S is inherited along with other hemoglobin variants, such as hemoglobin C or sickle cell β-thalassemia. In African Americans, 8% are heterozygous for hemoglobin S (sickle cell trait) and approximately 0.5% are homozygous for hemoglobin S. During conditions of low oxygen tension, these hemoglobin S molecules crystallize, distorting the cell into a crescent shape. These misshapen cells are unable to pass through the microvasculature, which results in capillary occlusion, thrombosis, and ultimately microinfarction. This cascade of events frequently occurs in the spleen. These episodes of vaso-occlusion and progressive infarction result in autosplenectomy. The spleen, which is usually hypertrophied early in life, typically atrophies by adulthood, although splenomegaly may occasionally persist.

Other causes of hemolytic anemia are the thalassemias. These are inherited as autosomal dominant traits and result from a defect in hemoglobin synthesis that causes variable degrees of hemolytic anemia. Splenomegaly, hypersplenism, and splenic infarction, common in sickle cell disease, are also seen commonly in the thalassemias.

Hypersplenism and acute splenic sequestration are life-threatening disorders in children with thalassemia and sickle cell disease. In these conditions, there may be rapid splenic enlargement, which results in severe pain and may require multiple blood transfusions. Patients with acute splenic sequestration crisis present with severe anemia, splenomegaly, and an acute bone marrow response, with erythrocytosis. There may be a concurrent decrease in hemoglobin levels, abdominal pain, and circulatory collapse. Resuscitation with hydration and transfusion may be followed by splenectomy in these patients. Hypersplenism related to sickle cell disease is characterized by anemia, leukopenia, and thrombocytopenia requiring transfusions; transfusions may be reduced by performing splenectomy. Symptomatic massive splenomegaly that interferes with daily activities may also be improved by splenectomy. Finally, in children with sickle cell disease who exhibit growth delay or even weight loss because of increased metabolic rate and whole-body total protein turnover, splenectomy may relieve these symptoms.

Splenic abscesses may also be seen in patients with sickle cell anemia. These patients present with fever, abdominal pain, and a tender enlarged spleen. Most patients with splenic abscesses will have a leukocytosis, as well as thrombocytosis and Howell-Jolly bodies indicating a functional asplenia. Salmonella and Enterobacter spp. and other enteric organisms are commonly seen in those with a splenic abscess. These patients require resuscitation with hydration and transfusion and may require urgent splenectomy after stabilization.